Abstract

3072

Neoamphimedine is a pyridoacridine that has a unique topoisomerase II-mediated activity. It facilitates catenation of plasmid DNA in vitro. Neoamphimedine also has potent anti-neoplastic activity in athymic mice. We utilized flow cytometry to further characterize the activity of neoamphimedine on the cell cycle of Chinese hamster ovary (CHO) cells. Neoamphimedine slightly decreased the amount of cells in G2/M-phase and increased the population in S-phase. We also compared the abilities of neoamphimedine and etoposide to produce chromosomal damage as observed in metaphase spreads. We found that increasing concentrations of etoposide correlated with increases in the fragmentation of chromosomes, and ultimately the production of pulverized chromosomes. No difference from control cells was observed for cells treated with neoamphimedine up to 7.5 μM, however, no metaphase spreads were observed at concentrations of 10 μM neoamphimedine. These data confirm that neoamphimedine differs form etoposide in its mechanism of killing in mammalian cells. As opposed to arresting cells in G2/M, neoamphimedine interferes with DNA synthesis. Instead of producing the chromosomal fragmentation characteristic of etoposide-topoisomerase II cleavable complex stabilization, neoamphimedine prevented chromosomal condensation. The mechanism of neoamphimedine cell killing in mammalian cells is significantly different from classical topoisomerase II cleavable complex stabilizing drugs.